Small Vessel Cerebrovascular DiseaseDietNOBrainNCT07329647
Targeting Neurovascular Coupling in Cognitive Decline Via Nitrate-Based Supplementation
A study testing Beetroot Juice - Active in people with Small Vessel Cerebrovascular Disease and Diabete Mellitus, run by University of Coimbra at 2 sites in Portugal.
Trial summary
Diet is established among the most relevant adjustable variables of human health in modern societies. The recognition by the World Health Organization of cognitive impairment and dementia associated with aging as one of the major public health challenges of our time, highlights the imperative need for a more… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Small Vessel Cerebrovascular Disease, Diabete Mellitus
- What is being tested?
- Beetroot Juice - Active
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 25 participants
- Where
- 2 sitesPortugal
- Study dates
- 9 May 2025to 31 Dec 2025
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Formal diagnosis of cerebral small vessel disease (grades 1 to 3 in the Age-Related White Matter Changes Scale as assessed by Computerized Tomography or Magnetic Ressonance Imaging - MRI) and patients at high risk for cerebral small vessel disease with diabetes mellitus;
- Subject has capacity and is capable of giving written informed consent;
- Subject is able to read, comprehend and record information written in Portuguese.
Who cannot join
- Vascular diseases other than cerebral Small Vessel Disease (cSVD);
- Stroke event less than 6 months ago;
- Unsuitable for MRI scanning because of presence of any standard MRI contraindication (e.g presence of a cardiac pacemaker, other medical implants or devices, or the presence of ferromagnetic metal foreign bodies);
- Needle phobia;
- Inability or intolerance to dietary polyphenol adjustment;
- Current smoker;
Show all 14Show fewer
- Alcohol abuse, drug abuse or use of drugs affecting cognitive assessment, such as sedatives, hypnotics, nootropic drugs, cholinergic drugs;
- Use of medications that may be contraindicated or interact with the high nitrate diet, such as nitroglycerin or nitrate preparations used for angina, or phosphodiesterase type 5 (PDE5) inhibitors, including sildenafil (Viagral);
- Patients previously diagnosed with dementia;
- Presence of congenital mental retardation and severe neurological and psychiatric diseases;
- Illiterate or severe visual or hearing impairment that may prevent patients from cooperating with cognitive assessment;
- Relevant depression or other unrelated serious mental illness;
- Severe cardiac, pulmonary, renal or hepatic insufficiency;
- Patients who have participated in other interventional clinical studies within the last 3 months, or are participating in other interventional clinical studies.
Trial locations and contacts
2 sites in 1 country. Contact the study team or a site near you to ask about taking part.
Portugal2 sites, 2 recruiting
- Recruiting
Institute for Nuclear Sciences Applied to Health (ICNAS), University of Coimbra
Coimbra
Miguel Castelo-Branco, +351 239488510, mcbranco@fmed.uc.pt
- Recruiting
Unidade de Saúde Local de Coimbra (ULS Coimbra)
Coimbra
João Sargento Freitas, MD PhD, (+351) 239400559, joaosargentofreitas@ulscoimbra.min-saude.pt
About this study
Official title: The Neurovascular Coupling as a Target for Cognitive Enhancement in Vascular Cognitive Decline Through an Innovative Nitrate-driven Dietary Supplementation.
Diet is established among the most relevant adjustable variables of human health in modern societies. The recognition by the World Health Organization of cognitive impairment and dementia associated with aging as one of the major public health challenges of our time, highlights the imperative need for a more comprehensive understanding of how different aspects of lifestyle, in particular diet, affect neural function and consequent cognitive performance throughout lifespan.
The brain is endowed with fine mechanisms for a precise spatial and temporal control of cerebral blood flow (CBF) according to neural activity, the neurovascular coupling (NVC). Mounting evidence from preclinical and human studies demonstrate that NVC dysfunction is a key early factor contributing to the pathogenesis of cognitive decline and vascular cognitive impairment (VCI) in aging and conditions associated with accelerated microvascular aging, such as cerebral small vessel disease (cSVD). Failure at any part of the NVC pathway disrupts CBF resulting in catastrophic depletion of oxygenation and energy supply to brain cells, and, in the long run, to neuronal dysfunction and cognitive impairment.
Read more
The investigators have shown that nitric oxide (NO) synthesized by neuronal nitric oxide synthase (nNOS) is a direct mediator of NVC and that decreased bioavailability of NO along aging compromised NVC and reduced local CBF. Shortly after the identification of nNOS as a source of NO for vasodilation in the brain, an alternative pathway for NO production independent of nNOS, relying on the sequential reduction of nitrate, the nitrate:nitrite:NO pathway, was unveiled.
Nitrate consumed in green leafy vegetables as part of a normal diet is bioactivated to nitrite and both compounds are permanent constituents of blood/tissues in animal species, influencing CBF and resulting in improvements in learning and memory in rodents and VCI patients. However, a critical question remains on whether NO produced from nitrite is functionally linked to neuronal activation. This is key to understanding whether dietary nitrate can be linked to neuronal-dependent CBF increases and cognitive performance.
The investigators and others have shown that upon excitatory stimulation, ascorbate is released from neurons being available for nitrite reduction and our preliminary data supports that NO bioavailability and CBF might be maintained independently of nNOS by the reduction of nitrite to NO in the brain extracellular space upon neuronal activation (unpublish data). This innovative mechanism functionally links the production of NO from nitrite to neuronal activation, triggering CBF increases and maintaining an operative NVC. A further facet is that, bridging diet and cognitive performance, this mechanism incorporates modulatory elements which is open to adjustment by diet via nitrate.
Thus, in this pilot trial a proof of concept study will be conducted to investigate the clinical impact of a dietary nitrate supplementation intervention in a clinical population with VCI due to small vessel disease, as measured by changes on NVC and cognitive performance.
The investigators hypothesise that functional NVC is maintained operative in VCI patients by increasing NO bioavailability in the extracellular space of the brain through a nitrate -rich diet that, in turn, supports an adequate CBF in response to neuronal activation, modulating the molecular mechanisms and cognitive performance of disease-related physiological and cognitive markers.
Read the detailed description
Professor João Laranjinha (CNC-UC) is the lead scientific contributor of the study.
- Being tested
- Beetroot Juice - Active, Beetroot Juice - Placebo
- Medical subject headings
- Cerebral Small Vessel Diseases, Diabetes Mellitus
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Beetroot Juice - ActiveDietary supplement
140 ml beetroot juice/day, corresponding to approximately 0.8 g of nitrate that will constitute a period of 2 weeks with a nitrate-diet (beetroot).
Beetroot Juice - PlaceboDietary supplement
140 ml nitrate-depleted beetroot juice/day, that will constitute a period of 2 weeks with a nitrate-depleted diet (beetroot).
| Study group | Role | What they receive |
|---|---|---|
| Nitrate rich beetroot juice | Experimental | Not described Receives: Dietary Supplement: Beetroot Juice - Active |
| Nitrate depleted beetroot juice | Placebo comparator | Not described Receives: Dietary Supplement: Beetroot Juice - Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Memory retrieval cognitive task (d prime)
Comparing changes from baseline after dietary nitrate supplementation (standardised beetroot juice) during 14 days versus the placebo condition.
Measured: From baseline to the end of treatment up to Week 4 and from baseline to the end of placebo up to Week 11.
Memory encoding Blood Oxigenation Level Dependent (BOLD) signal amplitude
Comparing changes from baseline after dietary nitrate supplementation (standardised beetroot juice) during 14 days versus the placebo condition.
Measured: From baseline to the end of treatment up to Week 4 and from baseline to the end of placebo up to Week 11.
Secondary outcomes (11)
Ascorbate concentration in the posterior cingulate cortex
Comparing changes in ascorbate concentration from baseline to after dietary nitrate supplementation (standardised beetroot juice) during 14 days versus the placebo condition.
Measured: From baseline to the end of treatment up to Week 4 and from baseline to the end of placebo up to Week 11.
Score on the Visual Analogue Scale of the health-related quality of life EQ-5D-5L questionnaire
Comparing changes from baseline after dietary nitrate supplementation (standardised beetroot juice) during 14 days versus the placebo condition on the score of the Visual Analogue Scale of EQ-5D-5L questionnaire, ranging from 0 to 100, where higher values mean better health related quality of life.
Measured: From baseline to the end of treatment up to Week 4 and from baseline to the end of placebo up to Week 11.
Nitrate concentration in the blood
Comparing changes in nitrate concentration from baseline to after dietary nitrate supplementation (standardised beetroot juice) during 14 days versus the placebo condition.
Measured: From baseline to the end of treatment up to Week 4 and from Week 7 to the end of placebo up to Week 11.
Glutathione concentration in the posterior cingulate cortex
Comparing changes in glutathione concentration from baseline to after dietary nitrate supplementation (standardised beetroot juice) during 14 days versus the placebo condition.
Measured: From baseline to the end of treatment up to Week 4 and from baseline to the end of placebo up to Week 11.
N-acetylaspartate concentration in the posterior cingulate cortex
Comparing changes in n-acetylaspartate concentration from baseline to after dietary nitrate supplementation (standardised beetroot juice) during 14 days versus the placebo condition.
Measured: From baseline to the end of treatment up to Week 4 and from baseline to the end of placebo up to Week 11.
Glutamate concentration in the posterior cingulate cortex
Comparing changes in glutamate concentration from baseline to after dietary nitrate supplementation (standardised beetroot juice) during 14 days versus the placebo condition.
Measured: From baseline to the end of treatment up to Week 4 and from baseline to the end of placebo up to Week 11.
Gamma-aminobutyric acid (GABA) concentration in the posterior cingulate cortex
Comparing changes in gamma-aminobutyric acid (GABA) concentration from baseline to after dietary nitrate supplementation (standardised beetroot juice) during 14 days versus the placebo condition.
Measured: From baseline to the end of treatment up to Week 4 and from baseline to the end of placebo up to Week 11.
Lactate concentration in the posterior cingulate cortex
Comparing changes in lactate concentration from baseline to after dietary nitrate supplementation (standardised beetroot juice) during 14 days versus the placebo condition.
Measured: From baseline to the end of treatment up to Week 4 and from baseline to the end of placebo up to Week 11.
Creatine concentration in the posterior cingulate cortex
Comparing changes in creatine concentration from baseline to after dietary nitrate supplementation (standardised beetroot juice) during 14 days versus the placebo condition.
Measured: From baseline to the end of treatment up to Week 4 and from baseline to the end of placebo up to Week 11.
Nitrite concentration in the blood
Comparing changes in nitrite concentration from baseline to after dietary nitrate supplementation (standardised beetroot juice) during 14 days versus the placebo condition.
Measured: From baseline to the end of treatment up to Week 4 and from Week 7 to the end of placebo up to Week 11.
S-nitrosothiols concentration in the blood
Comparing changes in S-nitrosothiols concentration from baseline to after dietary nitrate supplementation (standardised beetroot juice) during 14 days versus the placebo condition.
Measured: From baseline to the end of treatment up to Week 4 and from Week 7 to the end of placebo up to Week 11.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Jan 2026
- Study start9 May 2025
- Primary completion31 Dec 2025 (estimated)
- Study completion31 Dec 2025 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Small Vessel Cerebrovascular DiseaseStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 25 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Coimbra
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Miguel Castelo-Branco, University of Coimbra
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07329647
- Sponsor's protocol ID
- DietNOBrain01CNC
- Other IDs
- 2022.05454.PTDC
- Acronym
- DietNOBrain
- Status last verified
- Nov 2025
- First submitted
- 17 Nov 2025
- Last updated
- 9 Jan 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 9 Jan 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Neurovascular Coupling as a Target for Cognitive Enhancement in Vascular Cognitive Decline Through an Innovative Nitrate-driven Dietary Supplementation.
- ClinicalTrials.gov ID
- NCT07329647
- Acronym / sponsor ID
- DietNOBrain / DietNOBrain01CNC
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 25 participants (estimated)
- Lead sponsor
- University of CoimbraUniversity, hospital or other
- Study start
- 9 May 2025 (actual)
- Primary completion
- 31 Dec 2025 (estimated)
- Study completion
- 31 Dec 2025 (estimated)
- First posted
- 9 Jan 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Diet is established among the most relevant adjustable variables of human health in modern societies. The recognition by the World Health Organization of cognitive impairment and dementia associated with aging as one of the major public health challenges of our time, highlights the imperative need for a more comprehensive understanding of how different aspects of lifestyle, in particular diet, affect neural function and consequent cognitive performance throughout lifespan.
The brain is endowed with fine mechanisms for a precise spatial and temporal control of cerebral blood flow (CBF) according to neural activity, the neurovascular coupling (NVC). Mounting evidence from preclinical and human studies demonstrate that NVC dysfunction is a key early factor contributing to the pathogenesis of cognitive decline and vascular cognitive impairment (VCI) in aging and conditions associated with accelerated microvascular aging, such as cerebral small vessel disease (cSVD). Failure at any part of the NVC pathway disrupts CBF resulting in catastrophic depletion of oxygenation and energy supply to brain cells, and, in the long run, to neuronal dysfunction and cognitive impairment.
The investigators have shown that nitric oxide (NO) synthesized by neuronal nitric oxide synthase (nNOS) is a direct mediator of NVC and that decreased bioavailability of NO along aging compromised NVC and reduced local CBF. Shortly after the identification of nNOS as a source of NO for vasodilation in the brain, an alternative pathway for NO production independent of nNOS, relying on the sequential reduction of nitrate, the nitrate:nitrite:NO pathway, was unveiled.
Nitrate consumed in green leafy vegetables as part of a normal diet is bioactivated to nitrite and both compounds are permanent constituents of blood/tissues in animal species, influencing CBF and resulting in improvements in learning and memory in rodents and VCI patients. However, a critical question remains on whether NO produced from nitrite is functionally linked to neuronal activation. This is key to understanding whether dietary nitrate can be linked to neuronal-dependent CBF increases and cognitive performance.
The investigators and others have shown that upon excitatory stimulation, ascorbate is released from neurons being available for nitrite reduction and our preliminary data supports that NO bioavailability and CBF might be maintained independently of nNOS by the reduction of nitrite to NO in the brain extracellular space upon neuronal activation (unpublish data). This innovative mechanism functionally links the production of NO from nitrite to neuronal activation, triggering CBF increases and maintaining an operative NVC. A further facet is that, bridging diet and cognitive performance, this mechanism incorporates modulatory elements which is open to adjustment by diet via nitrate.
Thus, in this pilot trial a proof of concept study will be conducted to investigate the clinical impact of a dietary nitrate supplementation intervention in a clinical population with VCI due to small vessel disease, as measured by changes on NVC and cognitive performance.
The investigators hypothesise that functional NVC is maintained operative in VCI patients by increasing NO bioavailability in the extracellular space of the brain through a nitrate -rich diet that, in turn, supports an adequate CBF in response to neuronal activation, modulating the molecular mechanisms and cognitive performance of disease-related physiological and cognitive markers.
Detailed description
Professor João Laranjinha (CNC-UC) is the lead scientific contributor of the study.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Nitrate rich beetroot juice | Experimental | Dietary Supplement: Beetroot Juice - Active |
| Nitrate depleted beetroot juice | Placebo comparator | Dietary Supplement: Beetroot Juice - Placebo |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- Formal diagnosis of cerebral small vessel disease (grades 1 to 3 in the Age-Related White Matter Changes Scale as assessed by Computerized Tomography or Magnetic Ressonance Imaging - MRI) and patients at high risk for cerebral small vessel disease with diabetes mellitus;
- Subject has capacity and is capable of giving written informed consent;
- Subject is able to read, comprehend and record information written in Portuguese.
Key exclusion criteria (14 listed)
- Vascular diseases other than cerebral Small Vessel Disease (cSVD);
- Stroke event less than 6 months ago;
- Unsuitable for MRI scanning because of presence of any standard MRI contraindication (e.g presence of a cardiac pacemaker, other medical implants or devices, or the presence of ferromagnetic metal foreign bodies);
- Needle phobia;
- Inability or intolerance to dietary polyphenol adjustment;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Beetroot Juice - Active140 ml beetroot juice/day, corresponding to approximately 0.8 g of nitrate that will constitute a period of 2 weeks with a nitrate-diet (beetroot). | Dietary supplement | Nitrate rich beetroot juice |
| Beetroot Juice - Placebo140 ml nitrate-depleted beetroot juice/day, that will constitute a period of 2 weeks with a nitrate-depleted diet (beetroot). | Dietary supplement | Nitrate depleted beetroot juice |
Primary outcome
Memory retrieval cognitive task (d prime)
Time frame: From baseline to the end of treatment up to Week 4 and from baseline to the end of placebo up to Week 11.
Comparing changes from baseline after dietary nitrate supplementation (standardised beetroot juice) during 14 days versus the placebo condition.
Memory encoding Blood Oxigenation Level Dependent (BOLD) signal amplitude
Time frame: From baseline to the end of treatment up to Week 4 and from baseline to the end of placebo up to Week 11.
Comparing changes from baseline after dietary nitrate supplementation (standardised beetroot juice) during 14 days versus the placebo condition.
11 secondary outcomes
Ascorbate concentration in the posterior cingulate cortex
Time frame: From baseline to the end of treatment up to Week 4 and from baseline to the end of placebo up to Week 11.
Score on the Visual Analogue Scale of the health-related quality of life EQ-5D-5L questionnaire
Time frame: From baseline to the end of treatment up to Week 4 and from baseline to the end of placebo up to Week 11.
Nitrate concentration in the blood
Time frame: From baseline to the end of treatment up to Week 4 and from Week 7 to the end of placebo up to Week 11.
Glutathione concentration in the posterior cingulate cortex
Time frame: From baseline to the end of treatment up to Week 4 and from baseline to the end of placebo up to Week 11.
N-acetylaspartate concentration in the posterior cingulate cortex
Time frame: From baseline to the end of treatment up to Week 4 and from baseline to the end of placebo up to Week 11.
Glutamate concentration in the posterior cingulate cortex
Time frame: From baseline to the end of treatment up to Week 4 and from baseline to the end of placebo up to Week 11.
Gamma-aminobutyric acid (GABA) concentration in the posterior cingulate cortex
Time frame: From baseline to the end of treatment up to Week 4 and from baseline to the end of placebo up to Week 11.
Lactate concentration in the posterior cingulate cortex
Time frame: From baseline to the end of treatment up to Week 4 and from baseline to the end of placebo up to Week 11.
Creatine concentration in the posterior cingulate cortex
Time frame: From baseline to the end of treatment up to Week 4 and from baseline to the end of placebo up to Week 11.
Nitrite concentration in the blood
Time frame: From baseline to the end of treatment up to Week 4 and from Week 7 to the end of placebo up to Week 11.
S-nitrosothiols concentration in the blood
Time frame: From baseline to the end of treatment up to Week 4 and from Week 7 to the end of placebo up to Week 11.
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Jan 2026.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Beetroot Juice - Active in people with Small Vessel Cerebrovascular Disease and Diabete Mellitus, run by University of Coimbra at 2 sites in Portugal.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 9 Jan 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Portugal. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Miguel Castelo Branco, MD PhD (+351 239488510, mcbranco@fmed.uc.pt), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Memory retrieval cognitive task (d prime) (time frame: From baseline to the end of treatment up to Week 4 and from baseline to the end of placebo up to Week 11.). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Jan 2026.